The pharmacological possibilities for the treatment of acute cerebral stroke are very limited; until now, only thrombolitic therapy using a tissue plasminogen activator (tPA) can be moderately effective. Although the primary cellular damage caused by ischemia is not susceptible to treatment, there is the possibility of acting on secondary neuronal death in the penumbra zone, where a series of processes extending the damage occurs. Amongst them, particular attention has been paid to massive release of excitatory amino acids, and in this sense, drugs that prevent glutamate release, glutamate receptor antagonists, both NMDA and AMPA receptors, are effective in different experimental models.
At present, 14 different subtypes of serotonergic receptors are known. The 5-HT1A receptors, the localization
thereof being both presynaptic and postsynaptic, are the target of a group of anxiolytic drugs and perhaps they are also involved in the actions of specific anti-depressant drugs.
In ES 2052829 substituted aminoethyl tetralins and analogous heterocyclics are disclosed as selective agonists of the 5-HT1A subtype serotonergic receptors. One of the products disclosed in said document, BAYx3702, has shown experimentally, both in vitro (Suchanek et al., 1998; Ahlemeyer et al., 1999) and in vivo (Schaper et al., 2000; Torup et al., 2000; Kline et al., 2001), its neuroprotective effect due to its agonist action on the 5-HT1A receptor.
Spanish patent application No. 200102113, of the same authors of the present invention, discloses a series of compounds that behave as pure 5-HT1A receptor agonists although with only moderate potency, wherein neuroprotective action of this series of compounds could only be demonstrated using primary rat neuronal cultures.
The neuroprotective effect of the 5-HT1A receptor agonists may be due to different mechanisms amongst which the hyperpolarization in the activation of K+ channels, glutamate release inhibition (Matsuyama et al., 1996; Mauler et al., 2001) and the increase in BDNF neurotrophin expression (Galter et al. 2000) are highlighted.
The aforementioned data enables prediction of a new application for the compounds capable of activating the 5-HT1A receptors, namely, their use in the treatment of cerebral damage associated with ischemialhypoxia processes or traumatic incidents. Therefore, it is of great interest to have new agonist compounds of serotonergic 5-HT1A receptors which have neuroprotective effects and which can provide efficient treatment against cerebral damage associated with ischemialhypoxia processes or cranium-brain traumatic injuries.
No admission is made that any reference (or any portion of any reference) discussed above is prior art.